The advent of screening to identify children at increased risk for primary stroke using Transcranial Doppler (TCD) ultrasonography has improved the care of young patients with sickle cell anemia. Children with an abnormal time-averaged mean velocity (TAMV), defined as e 200 cm/sec, have a 44-fold increased stroke risk in comparison to those with TAMV below 200 cm/sec. The risk of primary stroke can be significantly reduced by placing patients with abnormal TCD velocities on a regimen of chronic erythrocyte transfusions and current standard management in the United States is to remain on transfusions indefinitely. Patients with conditional TCD velocities (TAMV 170 to 199 cm/sec) have a moderate risk for developing primary stroke, but the current standard of care for these patients is simply observation without specific therapy. A substantial percentage of these children with conditional TCD velocities will convert to the abnormal category, which is associated with an increased stroke risk. Our preliminary data suggest that hydroxyurea can reduce TCD velocities in children with sickle cell anemia, but further investigation is necessary to define the role of hydroxyurea in this clinical setting. Successful prevention of the conversion to abnormal TCD velocities would allow young patients to avoid exposure to prolonged blood transfusion and its associated toxicities (e.g., iron overload, alloimmunization, and infection). Prevention of TCD conversion would, therefore, result in a significant improvement in the medical management of children at moderate risk for stroke and ultimately reduce medical costs. While useful for developed nations like the US and European countries, this would represent an even more substantial improvement in medical care for children with SCA who live in developing nations with an inadequate or unsafe blood supply. We propose a Phase III randomized clinical trial of hydroxyurea therapy versus observation for children with sickle cell anemia (SCA) and conditional Transcranial Doppler (TCD) velocities, which is termed the Sparing Conversion to Abnormal TCD Elevation (SCATE) trial. SCATE will include three clinical sites: (1) St. Jude Children's Research Hospital in Memphis TN; (2) HEMORIO in Rio de Janeiro, Brazil; and (3) Sickle Cell Unit, Kingston Jamaica. In SCATE, we hypothesize that hydroxyurea treatment for children with conditional TCD velocities (170 - 199 cm/sec, moderate stroke risk) will be associated with a three-fold reduction in the incidence of conversion to abnormal TCD velocities (e 200 cm/sec, high stroke risk) by [30] months of therapy, as compared to children who receive observation alone. The primary aim of the SCATE trial is to compare standard therapy (observation) to alternative therapy (hydroxyurea) with the goal of preventing conversion from conditional to abnormal TCD velocities. Additional aims of the SCATE trial will include a description of the effects of standard versus alternative therapy on TCD velocities, on the incidence of stroke events and other non-stroke neurological events, and on quality of life scores. (End of Abstract) PUBLIC HEALTH RELEVANCE: Relevance Statement: Transcranial Doppler (TCD) screening identifies children with sickle cell anemia who have an increased risk of stroke. Although children with highly elevated (abnormal) TCD velocities receive therapeutic intervention, children with elevated (conditional) TCD values do not. In the SCATE study, we propose to treat children with conditional TCD velocities with hydroxyurea versus observation alone, to determine the beneficial effects of hydroxyurea in this clinical setting.